It has long been known that insulin and glucose play a role in determining glucose uptake by the liver, but recently a third factor, related to portal glucose delivery, has been implicated as a physiologic regulator of net hepatic glucose uptake. During feeding the portal glucose level exceeds the arterial glucose concentration and the efficiency with which the liver extracts glucose is enhanced. The hypothesis has been put forward that the portal vein glucose level is sensed by nerves terminals in the portal veins and that this information is relayed to the brain via vagal afferents where it is compared to input from arterial glucose sensors located elsewhere. We propose to further our understanding of the physiology of the "portal" glucose signal and by assessing its impact on the regulation of liver glucose metabolism. We propose to use arterio-venous difference and isotope (radioactive and stable) techniques to quantify the metabolic responses of the liver in the conscious dog. We will monitor net hepatic glucose uptake, net hepatic lactate balance, net hepatic CO2 production and glycogen formation as well as intrahepatic enzyme and metabolite levels in liver biopsies taken at the end of experiments. The proposal has four main aims. First, we propose to continue our characterizations of the "portal" signal by examining the waning of its effect (i.e. its off time). We will also extend our studies of insulin's effect on net hepatic glucose uptake. Second we propose to carry out studies to further examine the hypothesis that the CNS is involved in both the afferent and efferent sides of the feedback loop involving the "portal" signal. Third we will study the potential effects of the "portal" glucose signal on muscle (hindlimb A-V difference) and beta cell (pancreatic A-V difference) function. Lastly we will examine the ability of two other commonly ingested nutrients, amino acids and fructose, to modify the effects of the "portal" glucose signal on liver glucose metabolism. Data from the proposed experiments will increase our understanding of the role of the liver in postprandial nutrient disposition and should provide novel information concerning the role of the nervous system in metabolic regulation after feeding.